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Nitrosoureido nucleosides as potential inhibitors of nucleotide biosynthesis.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1988 Jan; Vol. 31 (1), pp. 250-4. - Publication Year :
- 1988
-
Abstract
- Several nitrosoureido nucleosides (3a, 3b, 5a, 7a, 7c, and 10a) designed as inhibitors of enzymes that metabolize pyrimidine nucleotides have been prepared and their chemical and biological properties studied. The methylnitrosoureas 3a and 3b were not significantly cytotoxic to H.Ep.-2 and L1210 cells in vitro but showed moderate activity in the P388 mouse leukemia screen (79% ILS for 3a and 56% ILS for 3b). The (chloroethyl)nitrosoureas 7a and 7c inhibited proliferation of L1210 cells, were cytotoxic to H.Ep.-2 cells, and demonstrated good activity against P388 in vivo (135% ILS with one 30-day survivor for 7a and 191% ILS with two 30-day survivors for 7c). Overnight exposure of L1210 cells to 7a and 7c resulted in cell enlargement accompanied by cell lysis. Macromolecular synthesis in enlarged cells, particularly RNA and protein synthesis, was markedly increased relative to that in untreated control cells. The half-lives of each of the nitrosoureas in pH 7 buffer was determined and compared with biological activity.
- Subjects :
- Animals
Carmustine pharmacology
Cell Division drug effects
DNA Replication drug effects
Drug Stability
Indicators and Reagents
Leukemia L1210 metabolism
Lomustine pharmacology
Mice
Neoplasm Proteins biosynthesis
Nitrosourea Compounds pharmacology
Nucleosides pharmacology
Nucleotides antagonists & inhibitors
Structure-Activity Relationship
Transcription, Genetic drug effects
Nitrosourea Compounds chemical synthesis
Nucleosides chemical synthesis
Nucleotides biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 31
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 3336023
- Full Text :
- https://doi.org/10.1021/jm00396a039